Efficacy of Resistance to Francisella Imparted by ITY/NRAMP/SLC11A1 Depends on Route of Infection

Natural resistance-associated macrophage protein (NRAMP) encoded by the gene is a membrane-associated transporter of divalent metal ions. Murine has two known alleles, a functional , which is found in DBA2/J, NOD/LtJ, and 129p3/J and related mouse strains, and a non-functional , that is found in C56Bl/6J (B6) and BALB/cJ mice. B6 mice congenic for (B6- ) are markedly resistant to the intracellular pathogens , and . We examined the host cell response and replication of in B6- mice. Bone marrow-derived macrophages from either B6- or B6 mice were both effectively invaded by live vaccine strain (LVS). However, at 16 hours post-infection (hpi), the number of LVS bacteria recovered from B6 macrophages had increased roughly 100-fold, while in B6- mice the number decreased 10-fold. When the mice were challenged intranasally (i.n.) B6 mice lost significant amounts (~15%) of weight, where as B6- mice lost no weight. Three days after infection in B6- mice, we failed to recover viable from the lungs, livers, or spleens. By contrast, B6 mice had bacterial burdens approaching 1 × 10 CFU/organ in all three organs. To further examine the degree of resistance imparted by expression, we challenged mice deficient in TLR2, TLR4, and TLR9, but expressing the functional Slc11a1 (B6- ). Surprisingly, B6- mice had no notable weight loss. Eighty percent of B6- mice yielded no detectable in any organ tested. Additionally, produced little detectable cytokine either in the lung or serum compared to B6 mice. Mice expressing survived even high doses (~80 LD ) of LVS inoculation. These data taken together serve to highlight that functional can compensate the lack of TLR2/4/9. Thus is a critical player in murine resistance to pulmonary infection, but not footpad infection.